NKX2.2 and KLF4 cooperate to regulate α-cell identity.

Transcription factors (TFs) are indispensable for maintaining cell identity through regulating cell-specific gene expression. Distinct cell identities derived from a common progenitor are frequently perpetuated by shared TFs, yet the mechanisms that enable these TFs to regulate cell-specific targets are poorly characterized. We report that the TF NKX2.

E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells.

The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific deletion mouse strain ( ) and found that is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux.

Impacts of Diabetes Self-Management Education and Support Programs in Hispanic Church Settings: A Cluster-Randomized Trial Comparing Faith-Based and Faith-Placed Approaches.

This study aimed to adapt evidence-based diabetes self-management education and support (DSMES) into a faith-based (FB) context for Hispanic communities and compare its effectiveness to a faith-placed (FP) approach using the church as a venue for DSMES delivery. A cluster-randomized trial was conducted among adults with type 2 diabetes from predominantly Hispanic churches. The churches were assigned to either the FB Group (nine churches, n = 146) or the FP Group (seven churches, n = 125).

Beyond the Synapse: and FMRP Molecular Mechanisms in the Nucleus.

(Fragile X messenger ribonucleoprotein 1), located on the X-chromosome, encodes the multi-functional FMR1 protein (FMRP), critical to brain development and function. Trinucleotide CGG repeat expansions at this locus cause a range of neurological disorders, collectively referred to as Fragile X-related conditions. The most well-known of these is Fragile X syndrome, a neurodevelopmental disorder associated with syndromic facial features, autism, intellectual disabilities, and seizures.

Genomic analysis of comprehensive next generation sequencing data to explore the criteria for MET amplification as an actionable biomarker in NSCLC.

Introduction: MET amplification (METamp) can be a de novo or acquired resistance driver; however, the definition of METamp that best captures patients who may respond to targeted therapy remains debated. We explored the genomic landscape of METamp NSCLC including degree of amplification, co-drivers, amplicon size, and outcomes to MET inhibitors.

Methods: Hybrid-capture NGS-based genomic profiling from 88,547 tissue and 12,428 liquid NSCLC samples were queried for METamp (copy number (CN) ≥ ploidy + 4, or amplification ratio (AmpRatio; [CN/sample ploidy] ≥ 3).

Cancer-related health behaviors during the COVID 19 pandemic in geographically diverse samples across the US.

Background: The COVID-19 pandemic involved business closures (e.g., gyms), social distancing policies, and prolonged stressful situations that may have impacted engagement in health behaviors.

Death and survival of gut CD4 T cells following HIV-1 infection ex vivo.

The gastrointestinal tract is ground zero for the massive and sustained CD4 T cell depletion during acute HIV-1 infection. To date, the molecular mechanisms governing this fundamental pathogenic process remain unclear. HIV-1 infection in the gastrointestinal tract is associated with chronic inflammation due to a disrupted epithelial barrier that results in microbial translocation.

Inactivation of GSK3β by Ser phosphorylation prevents thymocyte necroptosis and impacts Tcr repertoire diversity.

The assembly of Tcrb and Tcra genes require double negative (DN) thymocytes to undergo multiple rounds of programmed DNA double-strand breaks (DSBs), followed by their efficient repair. However, mechanisms governing cell cycle checkpoints and specific survival pathways during the repair process remain unclear. Here, we report high-resolution scRNA-seq analyses of individually sorted mouse DN3 and DN4 thymocytes, which reveals a G2M cell cycle checkpoint, in addition to the known G1 checkpoint, during Tcrb and Tcra recombination.

Oral Delivery of miR146a Conjugated to Cerium Oxide Nanoparticles Improves an Established T Cell-Mediated Experimental Colitis in Mice.

Dysregulated inflammation and oxidative stress are strongly implicated in the pathogenesis of inflammatory bowel disease. We have developed a novel therapeutic that targets inflammation and oxidative stress. It is comprised of microRNA-146a (miR146a)-loaded cerium oxide nanoparticles (CNPs) (CNP-miR146a).

Non-Genotoxic and Environmentally Relevant Lower Molecular Weight Polycyclic Aromatic Hydrocarbons Significantly Increase Tumorigenicity of Benzo[]pyrene in a Lung Two-Stage Mouse Model.

The World Health Organization has classified air pollution as a carcinogen, and polycyclic aromatic hydrocarbons (PAHs) are major components of air particulates of carcinogenic concern. Thus far, most studies focused on genotoxic high molecular weight PAHs; however, recent studies indicate potential carcinogenicity of the non-genotoxic lower molecular weight PAHs (LMW PAHs) that are found in indoor and outdoor air pollution as well as secondhand cigarette smoke. We hypothesize that LMW PAHs contribute to the promotion stage of cancer when combined with benzo[]pyrene (B[]P), a legacy PAH.

Pharmacokinetics of Oral Cannabinoid Δ8-Tetrahydrocannabivarin and Its Main Metabolites in Healthy Participants.

Background: Tetrahydrocannabivarin (THCV) is a phytocannabinoid commonly found in cannabis with potential pharmacological properties; however, its post-acute pharmacokinetics (PK) in humans have not been studied yet. THCV has two isomers, Δ9- and Δ8-THCV, which seem to have different pharmacological properties. We investigated the PK of the Δ8-THCV isomer after oral administration as part of a two-phase, dose-ranging, placebo-controlled trial in healthy participants.

Enhancement of Human Immunodeficiency Virus-Specific CD8 T Cell Responses with TIGIT Blockade Involves Trogocytosis.

Natural killer (NK) and CD8 T cell function is compromised in human immunodeficiency virus type 1 (HIV-1) infection by increased expression of inhibitory receptors such as TIGIT (T cell immunoreceptor with Ig and ITIM domains). Blocking inhibitory receptors or their ligands with monoclonal antibodies (mAb) has potential to improve antiviral immunity in general and facilitate HIV eradication strategies. We assessed the impact of TIGIT engagement and blockade on cytotoxicity, degranulation, and interferon-gamma (IFN-γ) production by CD8 T cells from persons living with HIV (PLWH).

DEAD/H Box 5 (DDX5) Augments E2F1-Induced Cell Death Independent of the Tumor Suppressor p53.

In almost all cancers, the p53 pathway is disabled and cancer cells survive. Hence, it is crucially important to induce cell death independent of p53 in the treatment of cancers. The transcription factor E2F1 is controlled by binding of the tumor suppressor pRB, and induces apoptosis by activating the gene, an upstream activator of p53, when deregulated from pRB by loss of pRB function.

Evolutionary Adaptations in Biliverdin Reductase B: Insights into Coenzyme Dynamics and Catalytic Efficiency.

Biliverdin reductase B (BLVRB) is a redox regulator that catalyzes nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductions of multiple substrates, including flavins and biliverdin-β. BLVRB has emerging roles in redox regulation and post-translational modifications, highlighting its importance in various physiological contexts. In this study, we explore the structural and functional differences between human BLVRB and its hyrax homologue, focusing on evolutionary adaptations at the active site and allosteric regions.

Meta-Analysis of MINIject vs. Two iStents as Standalone Treatment for Glaucoma with 24 Months of Follow-Up.

This study compares the long-term intraocular pressure (IOP)-lowering efficacy of standalone MINIject (iSTAR Medical, Belgium) suprachoroidal implantation and two iStent (Glaukos, CA, USA) trabecular bypass implantation using a systematic review and meta-analysis. Systematic review of standalone implantation of MINIject or iStent inject with at least 24 months of follow up. The mean and standard deviation of IOP and the number of IOP-lowering medications at baseline and at 24 months were extracted.

Catheter Ablation in Atrial Fibrillation: Recent Advances.

Atrial fibrillation (AF) is the leading cause of arrhythmia-related morbidity and mortality. Recurrent symptoms, hospitalizations, and cost burden to patients have necessitated treatments beyond antiarrhythmic drugs (AADs) for patients with AF. Catheter ablation has proven to be effective over medical therapy alone; however the recurrence rates for atrial tachyarrhythmias post-ablation remain significant, particularly in patients with persistent and long-standing persistent AF.

Navigating Hemorrhagic Shock: Biomarkers, Therapies, and Challenges in Clinical Care.

Hemorrhagic shock remains a leading cause of preventable death worldwide, with mortality patterns varying significantly based on injury mechanisms and severity. This comprehensive review examines the complex pathophysiology of hemorrhagic shock, focusing on the temporal evolution of inflammatory responses, biomarker utility, and evidence-based therapeutic interventions. The inflammatory cascade progresses through distinct phases, beginning with tissue injury and endothelial activation, followed by a systemic inflammatory response that can transition to devastating immunosuppression.

Leveraging Large Language Models in Radiology Research: A Comprehensive User Guide.

Large Language Models (LLMs) such as ChatGPT have been increasingly integrated into radiology research, revolutionizing the research landscape. The Radiology Research Alliance (RRA) of the Association for Academic Radiology (AAR) has convened a Task Force to develop this guide to help radiology researchers responsibly adopt LLM technologies. LLMs can improve various phases of the research process by helping to automate literature reviews, generate research questions, analyze complex datasets, and draft manuscripts.

Elevated Levels of Serum Alpha-2-Macroglobulin Associate with Diabetes Status and Incident Cardiovascular Disease in Type 1 Diabetes.

Background: Atherosclerotic cardiovascular disease (CVD) is a major cause of death in individuals with type 1 diabetes mellitus (T1DM). However, conventional risk factors do not fully account for the increased risk. This study aimed to investigate whether serum proteins associate with diabetes status and the occurrence of CVD in T1DM.

Nicotine and cannabis vaping among early high school adolescents: Disparities of use across sociodemographic characteristics and associations with psychosocial factors.

This study examines whether adolescent nicotine and cannabis vaping types (i.e., nicotine-only, cannabis-only, and dual use) differ across sociodemographic and school characteristics (e.

Mindfulness in the Medical Learning Environment: An Opportunity for the Struggling Learner?

Unlabelled: Mindfulness is defined as nonjudgmentally and purposefully paying attention in the present moment. Mindfulness may be a valuable tool in the remediation armamentarium, useful in bringing attention to an individual's struggles. However, such application has largely been unexplored.

Biofabrication of anisotropic articular cartilage based on decellularized extracellular matrix.

Tissue-engineered grafts that mimic articular cartilage show promise for treating cartilage injuries. However, engineering cartilage cell-based therapies to match zonal architecture and biochemical composition remains challenging. Decellularized articular cartilage extracellular matrix (dECM) has gained attention for its chondro-inductive properties, yet dECM-based bioinks have limitations in mechanical stability and printability.

Protocol for generating splice isoform-specific mouse mutants using CRISPR-Cas9 and a minigene splicing reporter.

Here, we present a protocol to alter the production of alternatively spliced mRNA variants, without affecting the overall gene expression, through CRISPR-Cas9-engineered genomic mutations in mice. We describe steps for designing guide RNA to direct Cas9 endonuclease to consensus splice sites, producing transgenic mice through pronuclear injection, and screening for desired mutations in cultured mammalian cells using a minigene splicing reporter. Splice isoform-specific mouse mutants provide valuable tools for genetic analyses beyond loss-of-function and transgenic alleles.

Functional and Cosmetic Considerations in Saddle Nose Deformity Repair.

The saddle nose deformity is associated with dorsal collapse and can have both function and cosmetic problems. The saddle nose can cause nasal obstruction by narrowing the nasal cavities, eliciting dynamic internal and external nasal valve narrowing, and abnormally widening the internal and external nasal valves altering airflow dynamics, sinonasal passageways, and olfaction. The saddle nose is challenging to treat due to skin contracture, lack of donor tissue, and difficulties in esthetic integration.

Moderate levels of folic acid benefit outcomes for cilia based neural tube defects.

Folic acid (FA) supplementation is a potent tool to reduce devastating birth defects known as neural tube defects (NTDs). Though effective, questions remain how FA achieves its protective effect and which gene mutations are sensitive to folic acid levels. We explore the relationship between FA dosage and NTD rates using NTD mouse models.